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1.  Is resistance to anti-tuberculosis drugs associated with type 2 diabetes mellitus? A register review in Beijing, China 
Global Health Action  2014;7:10.3402/gha.v7.24022.
China has a high burden of drug-resistant tuberculosis (TB) and diabetes mellitus (DM).
The objectives of this study were to determine the following in patients with culture-confirmed TB: 1) demographic characteristics and disease patterns in relation to the presence or absence of type 2 diabetes and 2) presence or absence of drug resistance to isoniazid (INH), rifampicin (RMP) or both in relation to duration of diabetes and control of diabetes.
This is a cross-sectional and retrospective study involving record reviews.
There were 621 patients with culture-positive TB, of whom 187 (30%) had previously known or new type 2 diabetes. In those with diabetes, there was a significantly higher proportion of males, persons aged ≥35 years and patients registered with new TB (p<0.05). Prevalence of multidrug-resistant TB (MDR-TB) was 6.2% in new patients (N=422) and 62.3% in previously treated patients (N=199), with no significant differences between those with and without diabetes. In patients with diabetes, there was no association of drug resistance with diabetes duration or disease control [assessed by fasting blood glucose (FBG) at 1 week].
A high proportion of patients with TB in a tertiary health facility, Beijing, China, had diabetes, but there was no association between type 2 diabetes and drug-resistant TB. Further prospective studies are needed to confirm these findings.
PMCID: PMC4028607  PMID: 24845213
diabetes mellitus; diabetes duration; diabetes control; tuberculosis; multidrug-resistant tuberculosis; China
2.  Excimer Laser Phototherapeutic Keratectomy for the Treatment of Clinically Presumed Fungal Keratitis 
Journal of Ophthalmology  2014;2014:963287.
This retrospective study was to evaluate treatment outcomes of excimer laser phototherapeutic keratectomy (PTK) for clinically presumed fungal keratitis. Forty-seven eyes of 47 consecutive patients underwent manual superficial debridement and PTK. All corneal lesions were located in the anterior stroma and were resistant to medication therapy for at least one week. Data were collected by a retrospective chart review with at least six months of follow-up data available. After PTK, infected corneal lesions were completely removed and the clinical symptoms resolved in 41 cases (87.2%). The mean ablation depth was 114.39 ± 45.51 μm and diameter of ablation was 4.06 ± 1.07 mm. The mean time for healing of the epithelial defect was 8.8 ± 5.6 days. Thirty-four eyes (82.9%) showed an improvement in best spectacle-corrected visual acuity of two or more lines. PTK complications included mild to moderate corneal haze, hyperopic shift, irregular astigmatism, and thinning cornea. Six eyes (12.8%) still showed progressed infection, and conjunctival flap covering, amniotic membrane transplantation, or penetrating keratoplasty were given. PTK is a valuable therapeutic alternative for superficial infectious keratitis. It can effectively eradicate lesions, hasten reepithelialization, and restore and preserve useful visual function. However, the selection of surgery candidates should be conducted carefully.
PMCID: PMC4033497  PMID: 24891945
3.  Rural Residents in China Are at Increased Risk of Exposure to Tick-Borne Pathogens Anaplasma phagocytophilum and Ehrlichia chaffeensis 
BioMed Research International  2014;2014:313867.
As emerging tick born rickettsial diseases caused by A. phagocytophilum and E. chaffeensis, anaplasmosis and ehrlichiosis have become a serious threat to human and animal health throughout the world. In particular, in China, an unusual transmission of nosocomial cases of human granulocytic anaplasmosis occurred in Anhui Province in 2006 and more recent coinfection case of A. phagocytophilum and E. chaffeensis was documented in Shandong Province. Although the seroprevalence of human granulocytic anaplasmosis (former human granulocytic ehrlichiosis, HGE) has been documented in several studies, these data existed on local investigations, and also little data was reported on the seroprevalence of human monocytic ehrlichiosis (HME) in China. In this cross-sectional epidemiological study, indirect immunofluorescence antibody assay (IFA) proposed by WHO was used to detect A. phagocytophilum and E. chaffeensis IgG antibodies for 7,322 serum samples from agrarian residents from 9 provinces/cities and 819 urban residents from 2 provinces. Our data showed that farmers were at substantially increased risk of exposure. However, even among urban residents, risk was considerable. Seroprevalence of HGA and HME occurred in diverse regions of the country and tended to be the highest in young adults. Many species of ticks were confirmed carrying A. phagocytophilum organisms in China while several kinds of domestic animals including dog, goats, sheep, cattle, horse, wild rabbit, and some small wild rodents were proposed to be the reservoir hosts of A. phagocytophilum. The broad distribution of vector and hosts of the A. phagocytophilum and E. chaffeensis, especially the relationship between the generalized susceptibility of vectors and reservoirs and the severity of the disease's clinical manifestations and the genetic variation of Chinese HGA isolates in China, is urgently needed to be further investigated.
PMCID: PMC4022244  PMID: 24877080
4.  Binding to WGR Domain by Salidroside Activates PARP1 and Protects Hematopoietic Stem Cells from Oxidative Stress 
Antioxidants & Redox Signaling  2014;20(12):1853-1865.
Aims: A component of the base excision repair pathway, poly(ADP-ribose) polymerase-1 (PARP1) functions in multiple cellular processes, including DNA repair and programmed cell death. We previously showed that Salidroside, a phenylpropanoid glycoside isolated from medicinal plants, prevented the loss of hematopoietic stem cells (HSCs) in native mice and rescued HSCs repopulating in transplanted recipients under oxidative stress. The aim of this study was to investigate the mechanism by which PARP1 activation by Salidroside maintains HSCs under oxidative stress. Results: We found that although there were no spontaneous defects in hematopoiesis in Parp1−/− mice, oxidative stress compromised the repopulating capacity of Parp1−/− HSCs in transplanted recipient mice. A biochemical study using truncated proteins lacking the defined functional domains of PARP1 showed that the tryptophan-glycine–arginine-rich (WGR) domain of PARP1 was critical for Salidroside binding and subsequent PARP1 activation under oxidative stress. Functionally, complementation of Parp1−/− HSCs with full-length PARP1WT, but not the PARP1R591K mutant in WGR domain restored Salidroside-stimulated PARP1 activation in vitro. Mechanistically, activated PARP1 by Salidroside enhanced the repopulating capacity of the stressed HSCs by accelerating oxidative DNA damage repair. Innovations and Conclusion: Our findings reveal the action of mechanism for Salidroside in PARP1 stimulation and a novel role of PARP1 activation in maintaining HSC function under oxidative stress. Antioxid. Redox Signal. 20, 1853–1865.
PMCID: PMC3967359  PMID: 24294904
5.  Transcriptome Analysis of the Hippocampus in Novel Rat Model of Febrile Seizures 
PLoS ONE  2014;9(4):e95237.
Febrile seizures (FS) are the most common type of convulsive events in infants and young children, but the precise underlying genetic mechanism remains to be explored. To investigate the underlying pathogenic factors in FS and subsequent epilepsy, alterations in gene expression between the two new strains of rats (hyperthermia-prone [HP] vs hyperthermia-resistant [HR]), were investigated by using the Whole Rat Genome Oligo Microarray. This process identified 1,140 differentially expressed genes (DEGs; 602 upregulated and 538 downregulated), which were analyzed to determine significant Gene Ontology (GO) categories, signaling pathways and gene networks. Based on the GO analyses, the modified genes are closely related to various FS pathogenesis factors, including immune and inflammatory responses and ion transport. Certain DEGs identified have not been previously examined in relation to FS pathogenesis. Among these genes is dipeptidyl peptidase 4 (DPP4), a gene closely linked to interleukin 6 (IL-6), which played a key role in the gene network analysis. Furthermore, sitagliptin, a DPP4 inhibitor significantly decreased epileptic discharge in rats, observed via electroencephalogram, suggesting an important role for DPP4 in FS. The effectiveness of sitagliptin in reducing seizure activity may occur through a mechanism that stabilizes cellular Ca2+ homeostasis. In addition, DPP4 expression may be regulated by DNA methylation. The hippocampal gene expression profiles in novel rat models of FS provides a large database of candidate genes and pathways, which will be useful for researchers interested in disorders of neuronal excitability.
PMCID: PMC3988142  PMID: 24736375
6.  Novel ZnO microflowers on nanorod arrays: local dissolution-driven growth and enhanced light harvesting in dye-sensitized solar cells 
Nanoscale Research Letters  2014;9(1):183.
ZnO nanostructures were manipulated, via a low-temperature solution process, from pure nanorod arrays to complex nanostructures of microflowers on nanorod arrays with adjusted quantities of flowers. We proposed the mechanism of local dissolution-driven growth to rationally discuss the novel growth process. These nanostructures were used as photoanodes in dye-sensitized solar cells. Compared to pure nanorod arrays, the nanorod array-microflower hierarchical structures improved the power conversion efficiency from 0.41% to 0.92%, corresponding to a 124% efficiency increase. The enhancement of the efficiency was mainly ascribed to the synergistic effect of the enhanced surface area for higher dye loading and the improved light harvesting from efficient light scattering. Present results provide a promising route to improve the capability of light-harvesting for ZnO nanorod array-based DSSCs.
PMCID: PMC3998216  PMID: 24731603
ZnO; Nanorod arrays; Microflowers; Dye-sensitized solar cells; Light harvesting
7.  The Outcome of Ipsilateral Hemihepatectomy in Mucin-Producing Bile Duct Tumors 
PLoS ONE  2014;9(4):e92010.
Mucin-producing bile duct tumors (MPBTs) are unusual, and we present our experience with nine surgically proven cases.
Between November 2002 and November 2012, 9 patients with surgically proven MPBTs (including history of relevant hepatobiliary surgery in 6 patients) were encountered. Their clinical, imaging, and surgical findings were reviewed.
The most common symptom is intermittent jaundice, which occurs in seven patients. The diagnostic specificity was 77.8% by preoperative Magnetic Resonance Cholangiopancreatography (MRCP). All the patients underwent ipsilateral hemihepatectomy or remnant hemihepatectomy, accompanied caudate lobectomy in one case and concomitant Roux-en-Y choledochojejunostomy in four cases. Postoperative course was uneventful. One patient, who had intra-abdominal recurrence 59 months after surgery, was received reoperation without recurrence at the last follow-up. The remaining eight patients were alive without disease recurrence.
Based on our follow up of 9 cases that were surgically treated for MPBTs, we conclude that ipsilateral hemihepatectomy is a safe surgical procedure with an observed recurrence risk of 11.1% and all long-term survival.
PMCID: PMC3984073  PMID: 24727803
8.  Combined Effects of TGFB1 +869 T/C and +915 G/C Polymorphisms on Acute Rejection Risk in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(4):e93938.
Transforming growth factor-beta 1(TGF-β1) is involved in the development of acute rejection (AR) episodes in solid organ transplant recipients; and a number of studies have been conducted to investigate the combined effects of human TGF-β1 gene (TGFB1) +869 T/C and +915 G/C polymorphisms on AR risk. However, the results obtained are inconclusive.
Eligible studies that investigated the haplotypic association between TGFB1 +869 T/C and +915 G/C polymorphisms and AR risk were comprehensively searched in the PUBMED, EMBASE, China National Knowledge Infrastructure, and Wanfang Database. Statistical analyses were performed by using STATA 12.0 and Review Manager 5.0.
Fourteen eligible studies with 565 AR cases and 1219 non-AR cases were included. Overall, a significantly decreased risk was detected in patients carried with intermediate producer (IP) haplotypes (T/C G/C, T/T G/C, and C/C G/G) and/or low producer (LP) haplotypes (C/C G/C, C/C C/C, T/T C/C, and T/C C/C) compared with high producer (HP) haplotypes (T/T G/G and T/C G/G; IP vs. HP: OR = 0.75, 95% CI, 0.58–0.96, P heterogeneity  = 0.238; IP/LP vs. HP: OR  = 0.77, 95% CI, 0.61–0.98, P heterogeneity  = 0.144). In addition, subgroup analysis by transplant types demonstrated a similar association in patients receiving heart transplant (IP vs. HP: OR  = 0.32, 95% CI, 0.14–0.73, P heterogeneity  = 0.790; IP/LP vs. HP: OR  = 0.41, 95% CI, 0.20–0.85, P heterogeneity  = 0.320).
The current meta-analysis and systematic review indicated that recipient TGFB1 HP haplotypes were significantly associated with an increased risk for AR in solid organ transplant recipients, particularly patients receiving cardiac allograft.
PMCID: PMC3976347  PMID: 24705444
9.  CBCT Evaluation of the Upper Airway Morphological Changes in Growing Patients of Class II Division 1 Malocclusion with Mandibular Retrusion Using Twin Block Appliance: A Comparative Research 
PLoS ONE  2014;9(4):e94378.
The purpose of this study was to evaluate the morphological changes of upper airway after Twin Block (TB) treatment in growing patients with Class II division 1 malocclusion and mandibular retrusion compared with untreated Class II patients by cone beam computed tomography (CBCT).
Materials and Methods
Thirty growing patients who have completed TB treatment were recruited into TB group. The control group (n = 30) was selected from the patients with the same diagnosis and without TB treatment. CBCT scans of the pre-treatment (T1) and post-treatment (T2) data of TB group and control data were collected. After three-dimensional (3D) reconstruction and registration of T1 and T2 data, the morphological changes of upper airway during TB treatment were measured. The statistical differences between T1 and T2 data of TB group as well as T2 and control data were accessed by t-test.
During the TB treatment, the mandible moved advanced by 3.52±2.14 mm in the horizontal direction and 3.77±2.10 mm in the vertical direction. The hyoid bone was in a more forward and inferior place. The upper airway showed a significant enlargement in nasopharynx, oropharynx and hypopharynx. In addition, the nasopharynx turned more circular, and the oropharynx became more elliptic in transverse shape. However, the transverse shape of the hypopharynx showed no significant difference. After comparison between T2 and control data, only the horizontal movement of the hyoid bone, the volumetric expansion of the oropharynx and hypopharynx, and changes of the oropharyngeal transverse shape showed significant difference.
Compared to the untreated Class II patients, the upper airway of growing patients with Class II division 1 malocclusion and mandibular retrusion showed a significant enlargement in the oropharynx and hypopharynx as well as a more elliptic transverse shape in the oropharynx, and the hyoid bone moved to an anterior position after TB treatment.
PMCID: PMC3976395  PMID: 24705466
10.  Transcription Factors GATA-4 and GATA-6: Molecular Characterization, Expression Patterns and Possible Functions During Goose (Anser cygnoides) Follicle Development 
The transcription factors GATA-4 and GATA-6, members of the GATA family, play an important role in ovarian cell proliferation, differentiation and apoptosis. In this study, the full-length coding sequences of goose GATA-4 and GATA-6 were cloned and characterized. GATA-4 and GATA-6 consist of 1236 and 1104 nucleotides encoding proteins with 411 and 367 amino acids, respectively. The deduced amino acid sequences of both proteins include two adjacent zinc finger domains with the distinctive form (CVNC-X17-CNAC)-X29-(CANC-X17-CNAC) and share 84.76% identity within this domain. In silico prediction together with matching of the high affinity RRXS(T)Y motif revealed that the GATA-4 protein might be phosphorylated predominantly at S233, but no phosphorylation site was found in the GATA-6 protein. Real-time quantitative PCR analysis showed that GATA-4 and GATA-6 mRNAs were co-expressed in goose follicles, moderately expressed in granulosa cells and weakly expressed in theca cells. The expression level of GATA-4 mRNA in healthy follicles was significantly higher than in atretic follicles or postovulatory follicles (P<0.01), and the expression level of GATA-6 mRNA in healthy follicles was significantly lower than in atretic follicles or postovulatory follicles (P<0.01). The expression level of GATA-4 mRNA in granulosa cells was downregulated during follicle development; the peak of expression occurred in the 8-10 mm follicles, and the lowest expression was in the F1 follicles. GATA-6 was upregulated and reached its peak expression in the F1 follicles. These results indicate that the molecular structural differences in goose GATA-4 and GATA-6 may be related to their different roles during follicle development.
PMCID: PMC3999398  PMID: 24531706
Cloning; Expression; GATA-4; GATA-6; Tianfu goose
11.  Overexpression of LAPTM4B-35: A Novel Marker of Poor Prognosis of Prostate Cancer 
PLoS ONE  2014;9(3):e91069.
Lysosome-associated protein transmembrane 4b-35 (LAPTM4B-35) is a member of the mammalian 4-tetratransmembrane spanning protein superfamily, which is overexpressed in several solid malignancies. However, the expression of LAPTM4B-35 and its role in the progression of prostate cancer (PCa) is unknown. The aim of the present study was to investigate the LAPTM4B-35 expression in PCa and its potential relevance to clinicopathological variables and prognosis.
Immunohistochemistry was used to determine the expression of LAPTM4B-35 protein in 180 PCa tissues in comparison with 180 normal benign prostatic hyperplasia (BPH) specimens. The correlation between the expression of the LAPTM4B-35 protein and the clinicopathologic characteristics of patients with PCa was analyzed.
Statistical analysis showed that LAPTM4B-35 expression was significantly elevated in PCa compared with the BPH controls. High LAPTM4B-35 staining was present in 71.11% of all the cases with PCa. The overexpression of LAPTM4B-35 was significantly associated with the lymph node metastasis, seminal vesicle invasion, PCa stage, higher Gleason score, higher preoperative PSA, and biochemical recurrence (BCR). The Kaplan-Meier survival analysis showed that the high expression of LAPTM4B-35 was related to the poor overall survival and BCR-free survival of patients with PCa. Multivariate Cox analysis showed that LAPTM4B-35 was an independent prognostic factor for both overall survival and BCR-free survival of patients with PCa.
Overexpression of LAPTM4B-35 may be associated with tumor progression and poor prognosis in PCa and thus may serve as a new molecular marker to predict the prognosis of PCa patients.
PMCID: PMC3961215  PMID: 24651764
12.  Polymorphisms of the LTA Gene May Contribute to the Risk of Myocardial Infarction: A Meta-Analysis 
PLoS ONE  2014;9(3):e92272.
The lymphotoxin-α (LTA), as one of the mediators of inflammation, may play an important role in the pathogenesis of myocardial infarction (MI). Genetic association studies (GAS) that have investigated the association between three common polymorphisms (A252G, G10A and C804A) of the LTA gene and susceptibility to MI have produced contradictory and inconclusive results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association of these polymorphisms with susceptibility to MI.
A literature search for eligible GAS published before October 15, 2013 was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and CNKI (China National Knowledge Infrastructure) databases. We performed a meta-analysis of fifteen case-control studies with a total of 22,549 MI patients and 16,105 healthy controls.
For LTA A252G, a borderline significant overall association was found, indicating that GG genotype may confer an increased susceptibility to MI compared to AA and AG genotypes. Based on an ethnicity stratification analysis, a significant association was observed in Asians, but not in Caucasians. For LTA G10A, no significant overall association was found. However, subgroup analysis based on ethnicity suggested that the 10A allele may confer a significant increased susceptibility to MI only in Asian populations. For LTA C804A, the combined results revealed a significantly increased susceptibility to MI for carriers of the 804A allele in both overall analysis and stratified analyses.
This meta-analysis shows that LTA C804A may be associated with an increased susceptibility to MI, whereas LTA A252G and G10A may confer a significant increased susceptibility to MI only in Asians. Thus, these polymorphisms of the LTA gene can probably be used with other genetic markers together to identify individuals at high susceptibility to MI especially in Asians.
PMCID: PMC3958506  PMID: 24642747
13.  Transcriptional Profiles of Cytokine/Chemokine Factors of Immune Cell-Homing to the Parasitic Lesions: A Comprehensive One-Year Course Study in the Liver of E. multilocularis-Infected Mice 
PLoS ONE  2014;9(3):e91638.
Pathogenesis of chronically developing alveolar echinococcosis (AE) is characterized by a continuous, granulomatous, periparasitic infiltration of immune cells surrounding the metacestode of Echinococcus multilocularis (E.multilocularis) in the affected liver. A detailed cytokine and chemokine profile analysis of the periparasitic infiltrate in the liver has, however, not yet been carried out in a comprehensive way all along the whole course of infection in E. multilocularis intermediate hosts. We thus assessed the hepatic gene expression profiles of 18 selected cytokine and chemokine genes using qRT-PCR in the periparasitic immune reaction and the subsequent adjacent, not directly affected, liver tissue of mice from day 2 to day 360 post intra-hepatic injection of metacestode. DNA microarray analysis was also used to get a more complete picture of the transcriptional changes occurring in the liver surrounding the parasitic lesions. Profiles of mRNA expression levels in the hepatic parasitic lesions showed that a mixed Th1/Th2 immune response, characterized by the concomitant presence of IL-12α, IFN-γ and IL-4, was established very early in the development of E. multilocularis. Subsequently, the profile extended to a combined tolerogenic profile associating IL-5, IL-10 and TGF-β. IL-17 was permanently expressed in the liver, mostly in the periparasitic infiltrate; this was confirmed by the increased mRNA expression of both IL-17A and IL-17F from a very early stage, with a subsequent decrease of IL-17A after this first initial rise. All measured chemokines were significantly expressed at a given stage of infection; their expression paralleled that of the corresponding Th1, Th2 or Th17 cytokines. In addition to giving a comprehensive insight in the time course of cytokines and chemokines in E. multilocularis lesion, this study contributes to identify new targets for possible immune therapy to minimize E. multilocularis-related pathology and to complement the only parasitostatic effect of benzimidazoles in AE.
PMCID: PMC3956718  PMID: 24637903
14.  Some Refinements and Generalizations of I. Schur Type Inequalities 
The Scientific World Journal  2014;2014:709358.
Recently, extensive researches on estimating the value of e have been studied. In this paper, the structural characteristics of I. Schur type inequalities are exploited to generalize the corresponding inequalities by variable parameter techniques. Some novel upper and lower bounds for the I. Schur inequality have also been obtained and the upper bounds may be obtained with the help of Maple and automated proving package (Bottema). Numerical examples are employed to demonstrate the reliability of the approximation of these new upper and lower bounds, which improve some known results in the recent literature.
PMCID: PMC3976784  PMID: 24772027
15.  The Effect of Multivitamin/Mineral Supplements on Age-Related Cataracts: A Systematic Review and Meta-Analysis 
Nutrients  2014;6(3):931-949.
Antioxidant vitamins supplements have been suggested as a strategy to decrease the risk of age-related cataract development. However, the results from observational studies and interventional trials of associations between antioxidant vitamins A, C, and E and cataract development have been inconsistent. We aim to evaluate the effectiveness of multivitamin/mineral supplements for decreasing the risk of age-related cataracts by conducting a systematic review and meta-analysis. In September 2013, we searched multiple databases to identify relevant studies including both cohort studies and randomized controlled trials (RCTs). A random-effects model was used to calculate the pooled relative risks (RR) with a 95% confidence interval (CI). Twelve prospective cohort studies and two RCTs were included. Pooled results from the cohort studies indicated that multivitamin/mineral supplements have a significant beneficial effect in decreasing the risk of nuclear cataracts (RR: 0.73; 95% CI: 0.64–0.82), cortical cataracts (RR: 0.81; 95% CI: 0.68–0.94), and any cataracts (RR: 0.66; 95% CI: 0.39–0.93). In addition, there were no decreases in the risk of posterior capsular cataracts (RR: 0.96; 95% CI: 0.72–1.20) or cataract surgery (RR: 1.00; 95% CI: 0.92–1.08). The two RCTs demonstrated that multivitamin/mineral supplements could decrease the risk of nuclear cataracts. There is sufficient evidence to support the role of dietary multivitamin/mineral supplements for the decreasing the risk of age-related cataracts.
PMCID: PMC3967170  PMID: 24590236
dietary supplements; cataract; vitamins; minerals; meta-analysis
16.  Prognostic role of phospho-PRAS40 (Thr246) expression in gastric cancer 
Archives of Medical Science : AMS  2013;10(1):149-153.
Phospho-PRAS40Thr246 (phosphorylated proline-rich Akt substrate of 40 kilodaltons at Thr246) is a biomarker for phosphatidylinositol 3-kinase (PI3K) pathway activation and AKT inhibitors sensitivity.
Material and methods
In this study, we immunohistochemically investigated the expression of phospho-PRAS40Thr246 in 141 gastric cancer tumors, and evaluated its clinicopathological and prognostic significance.
Sixty-four cases (45.4%) were defined as phospho-PRAS40Thr246 positive. Phospho-PRAS40Thr246 correlated positively with lymph node metastasis, lymphatic infiltration, vascular infiltration and shorter survival. Furthermore, phospho-PRAS40Thr246 is an independent prognostic factor for gastric cancer.
Our data suggest that phospho-PRAS40Thr246 was frequently expressed in gastric cancers, and correlated with malignant progression and poor prognosis of patients. PI3K pathway-targeted therapies should be considered in the future treatment of gastric cancers.
PMCID: PMC3953967  PMID: 24701227
PRAS40; phosphorylation; PI3K; prognosis; targeted therapy
17.  Clinical characteristics of congenital cervical atresia based on anatomy and ultrasound: a retrospective study of 32 cases 
To explore the clinical characteristics of congenital cervical atresia.
This retrospective analysis included 32 cases of congenital cervical atresia treated from March 1984 to September 2010. The anatomic location, ultrasonic features, surgical treatments, and outcomes were recorded.
Based on clinical characteristics observed during preoperative ultrasound and intraoperative exploration, congenital cervical atresia was divided into four types. Type I (n?=?22/32, 68.8%) is incomplete cervical atresia. Type II (n?=?5/32, 15.6%) defines a short and solid cervix with a round end; the structure lacked uterosacral and cardinal ligament attachments to the lower uterine body. Type III (n?=?2/32, 6.3%) is complete cervical atresia, in which the lowest region of the uterus exhibited a long and solid cervix. Type IV (n?=?3/32, 9.4%) defines the absence of a uterine isthmus, in which no internal os was detected, and a blind lumen was found under the uterus.
Observations of clinical characteristics of congenital cervical atresia based on the anatomy and ultrasound may inform diagnosis and treatment strategy.
PMCID: PMC3996070  PMID: 24555664
cervicovaginal operation; congenital cervical atresia; Müllerian duct anomaly
18.  MicroRNA-29a modulates axon branching by targeting doublecortin in primary neurons 
Protein & Cell  2014;5(2):160-169.
MicroRNAs (miRNAs) are endogenously expressed small, non-coding transcripts that regulate protein expression. Substantial evidences suggest that miRNAs are enriched in central nervous system, where they are hypothesized to play pivotal roles during neural development. In the present study, we analyzed miRNAs expression in mice cerebral cortex and hippocampus at different developmental stages and found miR-29a increased dramatically at postnatal stages. In addition, we provided strong evidences that miR-29a is enriched in mature neurons both in vitro and in vivo. Further investigation demonstrated that the activation of glutamate receptors induced endogenous miR-29a level in primary neurons. Moreover, we showed that miR-29a directly regulated its target protein Doublecortin (DCX) expression, which further modulated axon branching in primary culture. Together, our results suggested that miR-29a play an important role in neuronal development of mice cerebrum.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0022-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3956970  PMID: 24535747
miR-29a; doublecortin; glutamate receptor; mature neurons; axon branching
19.  MicroRNA-29a modulates axon branching by targeting doublecortin in primary neurons 
Protein & Cell  2014;5(2):160-169.
MicroRNAs (miRNAs) are endogenously expressed small, non-coding transcripts that regulate protein expression. Substantial evidences suggest that miRNAs are enriched in central nervous system, where they are hypothesized to play pivotal roles during neural development. In the present study, we analyzed miRNAs expression in mice cerebral cortex and hippocampus at different developmental stages and found miR-29a increased dramatically at postnatal stages. In addition, we provided strong evidences that miR-29a is enriched in mature neurons both in vitro and in vivo. Further investigation demonstrated that the activation of glutamate receptors induced endogenous miR-29a level in primary neurons. Moreover, we showed that miR-29a directly regulated its target protein Doublecortin (DCX) expression, which further modulated axon branching in primary culture. Together, our results suggested that miR-29a play an important role in neuronal development of mice cerebrum.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0022-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3956970  PMID: 24535747
miR-29a; doublecortin; glutamate receptor; mature neurons; axon branching
20.  Perioperative Heart-type Fatty Acid Binding Protein Levels in Atrial Fibrillation after Cardiac Surgery 
Postoperative atrial fibrillation (POAF) is common and associated with poor outcomes. Perioperative ischemia can alter arrhythmic substrate.
To demonstrate an association between perioperative measurement of heart-type fatty acid binding protein (HT-FABP), a sensitive marker of ischemic myocardial injury.
Blood samples from 63 inpatients undergoing coronary artery bypass surgery (CABG), valve surgery or both were obtained before and up to four days after surgery. Continuous telemetry monitoring was used to detect POAF. 59 patients had at least 3 HT-FABP measurements. The relation of ELISA-measured HT-FABP to POAF was assessed using joint logistic regression adjusted for age and surgery type.
Thirty five patients (55%) developed POAF; these were on average older (69.3 ± 10 vs. 60 ± 11 years, p=0.0019), with a higher prevalence of heart failure (43% vs. 17%, p=0.034), chronic obstructive lung disease (26% vs. 4%, p=0.017), preoperative calcium channel blocker use (29% vs. 7%, p=0.031) and more likely to undergo combined surgery (21% vs. 11%, p=0.049). The joint age- and CABG-adjusted model revealed that postoperative but not preoperative HT-FABP levels predicted POAF (coefficient 1.9 ± 0.87, p=0.03). Longer bypass time, prior infarction and worse renal function were all associated with higher postoperative HT-FABP.
A greater rise of HT-FABP is associated with atrial fibrillation after cardiac surgery, suggesting that ischemic myocardial damage is a contributing underlying mechanism. Interventions that decrease perioperative ischemic injury may also decrease the occurrence of POAF.
PMCID: PMC3687792  PMID: 23041578
Atrial Fibrillation; Postoperative; Biomarker; Ischemia; CABG; Valve Surgery
21.  Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines 
BMC Genomics  2014;15:93.
Two cytidine analogues, gemcitabine and cytosine arabinoside (AraC), are widely used in the treatment of a variety of cancers with a large individual variation in response. To identify potential genetic biomarkers associated with response to these two drugs, we used a human lymphoblastoid cell line (LCL) model system with extensive genomic data, including 1.3 million SNPs and 54,000 basal expression probesets to perform genome-wide association studies (GWAS) with gemcitabine and AraC IC50 values.
We identified 11 and 27 SNP loci significantly associated with gemcitabine and AraC IC50 values, respectively. Eleven candidate genes were functionally validated using siRNA knockdown approach in multiple cancer cell lines. We also characterized the potential mechanisms of genes by determining their influence on the activity of 10 cancer-related signaling pathways using reporter gene assays. Most SNPs regulated gene expression in a trans manner, except 7 SNPs in the PIGB gene that were significantly associated with both the expression of PIGB and gemcitabine cytotoxicity.
These results suggest that genetic variation might contribute to drug response via either cis- or trans- regulation of gene expression. GWAS analysis followed by functional pharmacogenomics studies might help identify novel biomarkers contributing to variation in response to these two drugs and enhance our understanding of underlying mechanisms of drug action.
PMCID: PMC3930546  PMID: 24483146
Cytidine analogues; Gemcitabine; Cytosine arabinoside; Lymphoblastoid cell lines; Expression array; Genome-wide SNPs; Genome-wide association study; Functional genomics; Translational research
22.  Serum complement C4b, fibronectin, and prolidase are associated with the pathological changes of pulmonary tuberculosis 
Mycobacterium tuberculosis infection can activate the immune system, leading to characteristic pathological changes such as inflammatory granuloma, caseous necrosis, and cavity formation.
Clinical data of 187 cases of pulmonary tuberculosis (PTB) were analyzed using statistical methods, while serum levels of complement C4b (C4b), fibronectin (FN), and prolidase (PEPD) were detected using the ELISA method among the control, minimal PTB, moderate PTB, and advanced PTB groups.
We found significantly higher levels of serum C4b and PEPD (P = 0.018, P = 0.003), and significantly lower levels of serum FN (P < 0.001) in PTB patients. Furthermore, the serum levels of 3 proteins were significantly different among 3 PTB groups. FN level was significantly higher in the moderate PTB group, compared with patients in the minimal and advanced PTB groups (P < 0.05, P < 0.01). PEPD level was significantly higher in the moderate PTB group, compared with the minimal PTB group (P < 0.05). Analysis of clinical data showed that serum albumin, C-reactive protein (CRP), prealbumin, and C4 were significantly higher (P < 0.05), while serum globulin was significantly lower in patients with PTB (P < 0.001). A significant negative correlation was found between C4b and albumin, prealbumin. On the other hand, a significant positive correlation was found between C4b and globulin, CRP, PEPD, as well as between PEPD and CRP (P < 0.05).
Our study showed that C4b, FN, and PEPD are associated with tissue damage, granuloma formation, and cavity formation, respectively, in patients with PTB. The present study provides a new experimental basis to understand the pathogenesis and pathological changes of PTB.
PMCID: PMC3913605  PMID: 24484408
Serum; Pulmonary tuberculosis; Complement C4b; Fibronectin; Prolidase; Granuloma; Cavity
23.  Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR Genetic Polymorphisms on Tacrolimus Metabolism in Chinese Renal Transplant Recipients 
PLoS ONE  2014;9(1):e86206.
Tacrolimus is a widely used immunosuppressive drug for preventing the rejection of solid organ transplants. The efficacy of tacrolimus shows considerable variability, which might be related to genetic variation among recipients. We conducted a retrospective study of 240 Chinese renal transplant recipients receiving tacrolimus as immunosuppressive drug. The retrospective data of all patients were collected for 40 days after transplantation. Seventeen SNPs of CYP3A5, CYP3A4, COMT, IL-10 and POR were identified by the SNaPshot assay. Tacrolimus blood concentrations were obtained on days 1–3, days 6–8 and days 12–14 after transplantation, as well as during the period of the predefined therapeutic concentration range. Kruskal–Wallis test was used to examine the effect of genetic variation on the tacrolimus concentration/dose ratio (C0/D) at different time points. Chi-square test was used to compare the proportions of patients who achieved the target C0 range in the different genotypic groups at weeks 1, 2, 3 and 4 after transplantation. After correction for multiple testing, there was a significant association of C0/D with CYP3A5*3, CYP3A4*1G and CYP3A4 rs4646437 T>C at different time points after transplantation. The proportion of patients in the IL-10 rs1800871-TT group who achieved the target C0 range was greater (p = 0.004) compared to the IL-10 rs1800871-CT and IL-10 rs1800871-CC groups at week 3 after transplantation. CYP3A5*3, CYP3A4 *1G, CYP3A4 rs4646437 T>C and IL-10 rs1800871 C>T might be potential polymorphisms affecting the interindividual variability in tacrolimus metabolism among Chinese renal transplant recipients.
PMCID: PMC3897654  PMID: 24465960
24.  Incremental Activation Detection for Real-Time fMRI Series Using Robust Kalman Filter 
Real-time functional magnetic resonance imaging (rt-fMRI) is a technique that enables us to observe human brain activations in real time. However, some unexpected noises that emerged in fMRI data collecting, such as acute swallowing, head moving and human manipulations, will cause much confusion and unrobustness for the activation analysis. In this paper, a new activation detection method for rt-fMRI data is proposed based on robust Kalman filter. The idea is to add a variation to the extended kalman filter to handle the additional sparse measurement noise and a sparse noise term to the measurement update step. Hence, the robust Kalman filter is designed to improve the robustness for the outliers and can be computed separately for each voxel. The algorithm can compute activation maps on each scan within a repetition time, which meets the requirement for real-time analysis. Experimental results show that this new algorithm can bring out high performance in robustness and in real-time activation detection.
PMCID: PMC3912890  PMID: 24511325
25.  Down-Modulation of Expression, or Dephosphorylation, of IG20/MADD in Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Resistant Thyroid Cancer Cells Makes Them Susceptible to Treatment with This Ligand 
Thyroid  2013;23(1):70-78.
The IG20/MADD gene is overexpressed in thyroid cancer tissues and cell lines, and can contribute to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) resistance. The ability of the MADD protein to resist TRAIL-induced apoptosis is dependent upon its phosphorylation by Akt. Interestingly, while TRAIL induces a significant reduction in the levels of phospho-Akt (pAkt) and phospho-MADD (pMADD) in TRAIL-sensitive cells, it fails to do so in TRAIL-resistant cells. In this study, we investigated if MADD phosphorylation by Akt was contributing to TRAIL resistance in thyroid cancer cells.
We determined the susceptibility of different thyroid cancer cell lines to TRAIL-induced apoptosis by fluorescence-activated cell sorting (FACS) analysis. We tested for various TRAIL resistance factors by FACS analyses or for IG20/MADD expression by quantitative reverse transcription–polymerase chain reaction. We determined the levels of pAkt and pMADD upon TRAIL treatment in thyroid cancer cells by Western blotting. We tested if down-modulation of IG20/MADD gene expression using shRNA or phosphorylation using a dominant negative Akt (DN-Akt) or pretreatment with LY294002, a PI3 kinase inhibitor, could help overcome TRAIL resistance.
BCPAP and TPC1 cells were susceptible, while KTC1 and FTC133 cells were resistant, to TRAIL-induced apoptosis. The differential susceptibility to TRAIL was not related to the levels of expression of death receptors, decoy receptors, or TRAIL. KTC1 and FTC133 cells showed higher levels of IG20/MADD expression relative to BCPAP and TPC1, and were rendered susceptible to TRAIL treatment upon IG20/MADD knockdown. Interestingly, upon TRAIL treatment, the pAkt and pMADD levels were reduced in TRAIL-sensitive BCPAP and TPC1 cells, while they remained unchanged in the resistant KTC1 and FTC133 cells. While expression of a constitutively active Akt in BCPAP and TPC1 cells rendered them resistant to TRAIL, pretreating KTC1 and FTC133 cells with LY294002 rendered them TRAIL-sensitive. Moreover, expression of a DN-Akt in KTC1 and FTC133 cells reduced the levels of pAkt and pMADD and sensitized them to TRAIL-induced apoptosis.
Our results show that pMADD is an important TRAIL resistance factor in certain thyroid cancer cells and suggest that down-modulation of either IG20/MADD expression or phosphorylation can render TRAIL-resistant thyroid cancer cells sensitive to TRAIL.
PMCID: PMC3539253  PMID: 22998497

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